The research in this Core focus on the interplay between oxidative stress and inflammation in the respiratory tract following exposure to environmental pollutants with the aim of uncovering mechanisms of lung injury and repair. The studies thematically fall into several related categories: particle induced oxidative stress and how molecules, cells, pre-existing disease, and age modulate oxidative stress. Dr. Oberdorster?s research focuses on particle-induced lung injury related to environmental and occupational exposures emphasizing two areas of interest: 1) ultra fine particles in high number but low mass concentrations cause adverse pulmonary effects in susceptible populations and ultrafine elemental carbon particles are used as surrogates for ambient particles; and, 2) poorly soluble particles of low toxicity encountered at high concentrations in the workplace pose risk of chronic injury. Recent work supports the notion that ultra fine particles may act as carriers for gas phase constituents which would be otherwise absorbed in the upper airways. Collaborations with Drs. Finkelstein and O?Reilly demonstrate development of tolerance against lethal exposures to polymer fumes consisting of ultra fine particles. Related work has attempted to define differences in response mechanisms between species of rodents. Dr. Finkelstein?s research addresses the elaboration of multiple mediators after the onset of lung injury, and whether related regulatory mechanisms are cell specific. Using both in vivo and in vitro models of injury (oxidant gases, ionizing radiation, and silica), expression of proinflammatory cytokines and chemokines are measured, and related changes in intracellular redox state and activation of specific families of transcription factors. Dr. O?Reilly, a new investigator in this group, has developed studies seeking to understand how oxidative stress influences proliferation of pulmonary epithelial cells. Hyperoxia has been used to increase expression of transforming growth factor and protein p53, which inhibit proliferation and promote apoptosis in transgenic mice and cell lines. His laboratory is also examining the genotoxic effects of hyperoxia via a DNA damage-dependent signal transduction pathway involving tumor growth factor (TGF)-beta. Dr. Phipps? studies are designed to define the role of fibroblast subpopulations in pulmonary inflammation and fibrosis resulting from hyperoxia, chemotherapeutic agents, or irradiation. Results indicate that a population of Thy 1+ fibroblasts mediate tissue repair while Thy 1- regulate inflammation leading to fibrosis. Work underway aims to determine how the fibroblast CD40 receptor is involved in regulating fibroblast proliferation, cytokine production, and lymphocyte interaction. Dr. Stripp?s program centers on lung defense against environmental pollutants and mechanisms of airway repair following injury. Studies have indicated that the neuroepithelial body (NEB) serves as a site for maintaining a population of reserve epithelial stem cells. New transgenic approaches are being developed to define the distinct airway stem cell populations during airway repair. The goals of the laboratory are to define Clara cell functioning and how it?s compromised during injury and repair. Drs. Utell and Frampton conduct controlled clinical studies examining the health effects of gaseous and particulate pollutants. Work has emphasized effects of oxidant gases (ozone and NO2), particulate nitrates and acid aerosols, siloxanes, hydrochlorofluorocarbons, and toluene on symptomology, lung function, airway inflammation, host defense, and cognitive functioning in healthy and susceptible human populations. Bronchoalveolar lavage, sputum analysis, and bronchial brush biopsies are used to define a variety of parameters of inflammation and disease.